A better
understanding of the interactions between hosts and
pathogenic fungi should improve the prognosis of fungal
infections. Our projects focus on Cryptococcus neoformans and Candida
albicans's pathogenicity by
studying the host (clinical and epidemiological studies,
animal models) and the fungus (virulence factors,
variability) sides, with an efficient interplay between
research activities and expertise done at the National
Reference Center.

Cryptococcus
neoformans

Cryptococcosis is a life-threatening disseminated
meningoencephalitis that occurs
in up to 18% of patients with AIDS in Africa and South
East Asia. C.
neoformans is surrounded by
a capsule made of polysaccharides, which is a major
virulence factor.

C.
neoformanscapsule (G.
Janbon): Our hypothesis is that
in addition to its presence, the variability of the
capsule structure should play a role in the yeast's
virulence. Genes coding for
proteins involved in the biosynthetic pathways of the
capsule have been cloned and
are studied for their involvement in pathophysiology and
for more basic projects (regulation of the
nucleotide-sugars transport in the vesicles, relationship
between the splicing of some specific genes and the
capsule structure…).

C.
neoformanscrossing
of the blood brain barrier (BBB) (F. Dromer): Little is
known on the mechanisms allowing C. neoformans to
cross the BBB. In collaboration with F. Chrétien
(INSERM EMI 0011, Créteil)
we are analyzing the mechanisms allowing
C. neoformans
crossing of the BBB. Preliminary
results demonstrate the contribution of monocytes
in C. neoformans
crossing of the BBB.

Host
response to CNS infection byC. neoformans (S. Mémet): Very
few data are available as regards to the role of host
cells, namely endothelial and glial cells, in crossing of
the BBB, dissemination of C.
neoformans, as well as in
induction/repression of an inflammatory response. We have
therefore initiated a thorough analysis of the
inflammatory signalling triggered by C. neoformans, with particular
emphasis on the role of the transcription factor
NF-κB, a major regulator of inflammation, innate and
acquired immunity. Experiments
are being conducted with two yeasts that induce either a
scanty (C.
neoformans) or a very
strong (C.
albicans) inflammatory
response. Preliminary results with a human BBB
endothelial cell model indicate that although both fungi
activate NF-κB in these
cells, the time-course of activation is
different.

Candida

Candida albicans is a commensal of the digestive tract responsible
for a wide range of infections in immunocompetent and
immunodeficient patients.

Biofilm
formation inC.
albicansandCandida glabrata (G. Janbon)

Biofilms are
tridimentional structures composed of microorganisms that
developed on various surfaces. Our objective in
collaboration with 4 units of the campus is to determine
molecular events leading to the development of biofilms
(PTR173). We have demonstrated that an adhesin encoding
gene was regulated by the sub-telomeric silencing
machinery, a signal activated during biofilm growth and
the Yak1p kinase. Our ongoing program is the study of
this important kinase.

Leishmaniasis
(P. Buffet)

We have been
involved in the set-up of 3 clinical trials in cutaneous
leishmaniasis, in collaboration with the Walter reed Army
Insitute of Research, the US Army Medical Material
Development Activity, and the Institut Pasteur in Tunis,
Tunisia. We are part of the National Reference Center for
Leishmania (Montpellier), providing real-time therapeutic
advice to clinicians facing complex decisions.
We are also collaborating with the
Immunophysiology & Intracellular Parasitism Unit (IP)
on the evaluation of topical agents’ efficacy in
experimental cutaneous leishmaniasis.

National Reference Center
Mycoses and Antifungals (F. Dromer, O.
Lortholary): Our missions include (1) expertise in the
identification and characterization of pathogenic fungi
and advice for the management of patients with severe
mycoses; (2) epidemiological survey of all rare, severe
or exotic mycoses as well as of the emergence of
resistance to antifungal drugs, with notification through
a secured website RESOMYC. (3) design of new typing
systems (4) phylogenetic
studies.